Substance use disorders are complex. Genetics, environment, and exposure all play a role in drug use. Recently, there has been evidence that another factor may play a role in substance use disorders: the gut-brain axis. The gut-brain axis is the bidirectional communication pathways between the gut microbiome and the brain.
Our most recent publication, led by Dr. Sierra Simpson, provides new evidence that alterations of the gut microbiome directly impact the neuronal ensembles recruited during both intoxication and withdrawal from oxycodone.
To put this concept into perspective, imagine that a patient goes in for a routine surgery. They are likely to be prescribed antibiotics and some form of pain management, simultaneously. Both antibiotics and opioids drastically impact the makeup of the gut microbiome. Opioids reduce the transit time of gut contents, while antibiotics kill off both protective and pathogenic bacteria. Microbes that are usually present are no longer there to fill the niche that can include a wide range of functions, from digesting fiber to secreting signaling molecules. Some of these molecules are known to have direct impact on the brain, but little has been done to show the direct impact of microbiome depletion on the brain circuits involved in opioid addiction.
This led the team to ask: “Are the neuronal populations being recruited in depleted animals different from those in intact animals? Does it impact how the brain experiences intoxication and withdrawal?”
The idea for this study started one day, when "Sierra just walks into my lab and asks me if I'd be interested in exploring potential connections between the gut microbiome and what my lab typically studies–drug abuse and addiction," said Olivier George, PhD, associate professor of psychiatry at University of California San Diego School of Medicine. "I was reluctant at first. After all, I figured if there was something there, someone would've discovered it by now.” But he decided to give it a try.
To explore these questions, the team used a cocktail of antibiotics to reduce the quantity and variety of gut microbes present in a subset of rats. Then, the animals were exposed to opioids, enough to make them dependent and to exhibit withdrawal signs. And that’s when the story gets interesting.
"To me, the most surprising thing was that the rats all seemed the same on the surface," George said. "There weren't any major changes in the pain-relieving effect, or symptoms of withdrawal of opioids, or other behavior between the rats with and without gut microbes."
At first, Sierra thought that maybe she would have to revise her hypothesis. That is, until she looked at the brains of the treated animals. Regions that are involved in withdrawal, such as the central amygdala, had fewer activated neurons than brains from rats with normal microbiomes. The intoxicated group also exhibited changed in regions involved in arousal and stress. Finally, after months of carefully counting the active neurons in each state, it became clear that alterations of the gut microbiome drastically changed how the brain was responding to drugs.
Shifting how the animals experienced both the rewarding effects of opioid intoxication as well as the negative effects of withdrawal could potentially increase their risk of further drug abuse. Though there were no observed changes in behaviors of these animals, this study sets the framework for the further investigation of these mechanisms, and those changes in the brain may alter other behaviors.
"Not only does this study suggest that gut microbes may play a role in drug addiction; if we find similar effects in humans,” George says, “it may also change the way we think about co-prescribing antibiotics and pain killers." He continues, "The way a person's gut microbes are affected could make them more or less sensitive to the opioids. The key now will be looking for biomarkers, so we can predict how a person might respond before we treat them."
The team is currently exploring these questions further, using other models within the lab in a strain of rats with heterogeneous backgrounds, to better model the genetic diversity of the human population.
“Antibiotic Depletion of the Microbiome Alters the Recruitment of Neuronal Ensembles of Oxycodone Intoxication and Withdrawal”. by Sierra Simpson, Adam Kimbrough, Brent Boomhower, Rio McLellan, Marcella Hughes, Kokila Shankar, Giordano de Guglielmo and Olivier George. eNeuro doi:0.1523/ENEURO.0312-19.2020